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Clinical Trials Cooperative Group Program Guidelines, August 1996IV. STUDY DEVELOPMENT IV.1. General Considerations IV.1. GENERAL CONSIDERATIONS Under the cooperative agreement mechanism, the Group and the NCI share the responsibility for ensuring that the best and most important clinical research is conducted, within the limits of available research support and finite patient resources. Similarly, both the Groups and the NCI share responsibility for ensuring that the Clinical Trials Cooperative Group Program functions as efficiently as possible. Definitive clinical trials should usually constitute the major portion of a Group's activities; they should always serve as the ultimate goal of preliminary developmental trials. It is essential that important, original, and feasible treatment questions be posed, that study questions be answerable in a reasonable period of time, and that the methodology of each study be sound. While all treatment modalities and cancer sites are appropriate for Group study, there is no requirement for each Group to be active in every modality and/or disease. Proper integration of diagnostic or other support modalities is essential, with standards of quality control as rigorous as those applied to treatment modalities. IV.2. SPECIFIC GROUP RESPONSIBILITIES
In most Groups the process of study generation begins at the
level of a disease or modality committee, which develops specific
experiments ultimately embodied in Group protocols. This proven
organizational approach provides a forum for investigators who
share a common area of interest, and an arena in which various
ideas must compete if they are to gain the status of a Group
study. IV.2.A. Development of Research Plans The Group and its research committees should develop, articulate, and follow a comprehensive research plan which summarizes the Group's specific objectives and lines of investigation for each disease or modality that it chooses to study. The purpose of this plan is to focus attention on long-term goals, and to aid the Group in prioritization of competing research ideas. The plan will frequently include small developmental/pilot studies, Phase II studies, as well as large-scale Phase III efforts (see section IV.3.A. regarding national priorities), all designed to take advantage of the Group's experience, expertise, resources, and clinical opportunities. These comprehensive research plans for each disease and/or
modality committee will be a major focus of the peer review
process when the Group is reviewed. IV.2.B. Flexibility While it is important to establish disease and modality plans,
and to implement specific studies in these contexts, the Groups
must also be flexible enough to permit creative investigation in
light of unexpected opportunities. The potential to respond
quickly to promising data and innovative ideas is an important
facet of the Clinical Trials Cooperative Group Program, and
Groups should modify plans when the data warrant. IV.2.C. Collaboration with CTEP Staff CTEP staff assess particular research trials from the
perspective of all scientific opportunities competing for support
by the Program, and in the context of established national
research priorities. Because of the major effort and commitment
of resources required to develop and successfully mount
definitive Phase III trials, CTEP staff should be involved by the
Group in the planning of such trials at the earliest possible
stage (see section IV.3.A. and B.). The same applies to the
research plans referred to in section IV.2.A., and especially to
broad new initiatives undertaken by the Group. IV.2.D. Prioritization by the Group In addition to providing an environment for the development
and conduct of good clinical trials, the Group executive
leadership has the responsibility for managing the research
resources of the entire Group. This task is best accomplished by
maintaining a clear sense of scientific priorities for the
competing ideas of all of the Group's research committees. As
each disease and/or modality committee formulates plans and
specific protocols, the Group leadership must prioritize the
plans and studies in the context of the Group's overall
scientific objectives. IV.2.E. Efficiency of Study Development The administrative structure of a Group should support rapid
development and activation of the most important protocols. In
this regard continual assessment of overall priorities is
essential. IV.2.F. Timely Completion of Studies - Participation in
Intergroup Studies It is essential that all Group studies arrive at their conclusions rapidly enough to be meaningful in light of the rate of evolution of new ideas regarding the disease under study. This goal often can be met by a single Group. When it cannot, however, Intergroup collaboration is a more appropriate method of investigation. Intergroup studies as components of a defined research plan are neither more nor less valuable than single-Group studies; they are, however, more appropriate than single-Group trials that cannot satisfy the requirement for timely completion. A Group is entitled to special recognition by peer review when its investigators have played a major role in the development, leadership, or accrual for Intergroup studies. Intergroup study guidelines, Guidelines for the Conduct of
Intergroup Studies, (revised December, 1993 - available from
CTEP staff) have been developed by the Groups and endorsed by
CTEP with the intent of facilitating this mechanism of trial
conduct. In general, Intergroup collaboration is most likely to
succeed when all parties have had an opportunity to participate
in the entire process of study development, thereby developing a
sense of commitment to the study, and when the mechanics of trial
conduct are established from the inception of the study. IV.2.G. Maximizing Available Financial Resources Each Group should attempt to accomplish its major goals within
the limits of its peer-reviewed and approved scope of work and
its allocated budget. This includes reprogramming non-restricted
funds when necessary to support initiatives of the highest
priority. The responsibility for overall financial management also includes careful consideration of the financial impact of research plans, not only on patient care costs but also on the short term and long term costs associated with data collection, data analysis, quality assurance and on-site auditing. To the extent consistent with good science, cost containment at all levels of study conduct should be a factor in protocol design. IV.3. SPECIFIC CTEP RESPONSIBILITIES
IV.3.A. Coordinate National Priorities For common and/or treatable malignancies CTEP staff will be
responsible for maintaining a clear set of national priorities
for treatment research, based upon substantial consultation with
experts in the field. In selected disease or modality areas,
particularly when spontaneous Intergroup planning does not occur,
CTEP staff will coordinate the organization of ad hoc
strategy committees which will identify in general terms research
issues in need of study in major Phase III trials and establish
priorities among those competing ideas. These committees will be
composed of investigators with established expertise in the
particular field, and in most instances will consist primarily of
extramural scientists drawn from the Groups. CTEP staff will be
responsible for prompt dissemination of the recommendations of
these committees, particularly their statements of research
priorities. Phase III studies developed by the Groups should be
responsive to these priorities, or be equally worthy of NCI
support. Under nearly all circumstances, however, studies are
written by Group investigators and represent the work of the
Groups. IV.3.B. Participate in Major Study Development CTEP staff will continue to be active participants in the
development of studies that require a major commitment of
financial resources and/or patient accrual. CTEP staff will serve
as a resource to the Groups for information on national
priorities and ongoing efforts within the scientific community.
CTEP staff will formally review study concepts for programmatic
interest, and for conceptual duplication with ongoing research
elsewhere; to the extent possible CTEP staff will also assess
feasibility and proposed methodology (see IV.3.E.). CTEP staff
can most effectively facilitate Intergroup collaboration or
marshal special resources early in the process of study
development. IV.3.C. Maintain Active Scientific Liaison Each Group has a staff physician from the Clinical
Investigations Branch, CTEP, who acts as liaison for scientific
matters. S/he serves as the primary contact for scientific
inquiries, information concerning the content of specific
protocol or concept reviews, and feedback on general scientific
direction of Group committees or on Group plans. The scientific
liaison monitors the Group's progress and attends the Group's
meetings. S/he is responsible for knowledge of the Group's
repertoire of studies, areas of special interest and expertise,
and unique resources. S/he is also responsible for providing the
NCI Program Director with ongoing assessments of Group activity
from an administrative perspective (the scientific liaison has a
general knowledge of the Group's budget, but primary
responsibility in that area rests with the NCI Program Director,
section IX.1, and the Grants Management Specialist, section
IX.2). IV.3.D. Coordinate Investigational Agent Development The clinical development of new anticancer agents is a highly important utilization of Group resources, when carried out as a component of an overall strategy for study of a given disease. The Groups are a vital component of the research apparatus necessary for the clinical development of the many new investigational agents sponsored by the DCTD. The DCTD responsibilities for this development are shared by
all Branches of CTEP. The Investigational Drug Branch is
responsible for 1) planning within CTEP and with members of the
extramural community overall strategies for new agent studies in
specific tumor types; and 2) coordinating and monitoring the
trials of new agents developed by the DCTD. The Pharmaceutical
Management Branch provides for the distribution of
investigational new agents for which DCTD is the sponsor. The
Regulatory Affairs Branch maintains close contact and ongoing
dialogue with the pharmaceutical industry and with the Food and
Drug Administration (FDA) in order to ensure that new agent
development complies with Federal regulations and proceeds in a
coordinated way. The Clinical Investigations Branch is involved
in promoting comparative clinical trials evaluating treatment
strategies using new agents versus appropriate control therapies.
The Biometric Research Branch assesses proposed designs for
evaluating the benefits of investigational agents. The Clinical
Trials Monitoring Branch verifies adherence by the Groups to the
quality assurance procedures of investigational agent trials.
CTEP utilizes a system of Letters of Intent (LOIs) as a mechanism
for developing rational strategies for drug development studies.
The Investigator's Handbook, A Manual for Participants in
Clinical Trials Sponsored by the Division of Cancer Treatment and
Diagnosis, National Cancer Institute, revised 10/93, fully
describes the process for the clinical development of
investigational agents and summarizes the responsibilities of
investigators conducting these trials. IV.3.E CTEP Protocol Review All protocols using Group resources must be filed with the CTEP Protocol and Information Office. Cooperative Group protocols in the following categories must be reviewed and approved by CTEP before activation:
Large clinical trials involve years of effort and a substantial expenditure of resources. When planning a Phase III trial, Group Headquarters must submit a concept summary for CTEP review, including an overview of the study objectives, a brief review of the background or justification for the study, a general description of the patient population, a treatment schema and an estimate of the required accrual. In the event of an Intergroup study, the Coordinating Group must submit the concept, also providing a list of the participating Groups and identification of the study chairman, study coordinators from each participating Group, and modality co-chairs. CTEP will then formally review and provide a written Program Concept Review commenting on study design and programmatic interest. Accordingly, protocol review will be the final step in an interactive process, at least for large Phase III trials. Major conceptual disagreements should not occur at this stage, but rather have been resolved earlier. Protocol review should serve to check the details of a particular clinical trial prior to its activation. To expedite appropriate review, each protocol should contain all the information necessary for any reviewer to make an informed decision about its merits. A brief statement concerning the place of a specific protocol in the Group's disease strategy is particularly important for pilot and Phase II studies, and should be included with the background and scientific rationale. Additional details on protocol content can be found in the Investigator's Handbook. NOTE: Each protocol should address gender and minority inclusion as stated in the NIH Guidelines on the Inclusion of Women and Minorities as Subjects in Clinical Research and PHS 398, Rev. 5/95; when Phase III clinical trials are proposed, investigators must show whether clinically important gender or race/ethnicity differences are to be expected, and the trials should be designed to accommodate any differences (PHS 398, Rev. 5/95, pages 17 and 28-3 0.) The CTEP Protocol Review Committee (PRC) meets weekly; it is chaired by the DCTD Associate Director responsible for CTEP (AD, CTEP). The membership includes the entire CTEP professional staff and occasional invited consultants. The PRC bases its judgments on several factors, including: 1. The importance and relevance of the issue being investigated; 2. The soundness of the study's scientific rationale; 3. The adequacy of the design to evaluate the specific research question(s); 4. The appropriateness of statistical methodology (early stopping, sequential design, etc); 5. The timeliness with which the trial will be completed; 6. The adequacy of the modality sections (e.g., chemotherapy, surgery, radiation therapy, pathology) in describing the study's operation; 7. Representation as Study Chairs or Co-Chairs of investigators within the disciplines involved in the study (e.g., medical, pediatric, surgical, gynecologic); 8. The Group's prior performance in similar studies; 9. The apparent feasibility of the study; 10. The resources required to mount the trial (dollars, patients, agents, etc.); 11. Regulatory, human subjects protection, and administrative and contractual concerns, (e.g., industry collaboration, NCI technology transfer objectives); and 12. Adequacy of plans to include both genders and minorities
and their subgroups as appropriate for the scientific goals of
the research. Plans for the recruitment and retention of subjects
will also be evaluated. Protocols are reviewed within four weeks following receipt by CTEP. The results of the review are provided in a "consensus review", which is sent to the Group. The PRC's options include: 1. approval as written; 2. approval with recommendations; 3. request for clarifications; 4. request for revisions; or 5. disapproval. In general, disapproval implies that a study is seriously
flawed in its rationale or design, or seriously in conflict with
national priorities and without sufficient redeeming features of
its own. NCI-awarded funds may not be used to support protocols
disapproved by CTEP. All disagreements with PRC review, including
disapproval, may be appealed to CTEP. If an unresolvable
disagreement persists, an arbitration procedure may be invoked
which is described in the Terms and Conditions of Award of each
cooperative agreement. IV.3.F. CTEP Amendment Review Any change to the protocol document subsequent to its approval
by CTEP must be submitted in writing for review and approval
prior to implementation. These procedures are outlined in the Investigator's Handbook.
IV.3.G. Facilitate Completion Of Important Trials CTEP staff will take an active role in promoting the timely
completion of important studies, for example by encouraging and
facilitating Intergroup collaboration when appropriate, or by
assisting in the mobilization of other available and required
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